Treatment of Epstein Barr infection

ABSTRACT

A method of treating Epstein Barr virus infection in humans by administering a pharmaceutically effective amount of an antiviral agent selected from a group consisting of acyclovir, famciclovir, valacyclovir and a pharmaceutically acceptable salt thereof is provided.

BACKGROUND OF THE INVENTION

Epstein Barr Virus (EBV) is a herpesvirus that infects 95% of the population world wide. EBV is the causative agent for infectious mononucleosis and is also closely associated with nasopharyngeal carcinoma, Burkitt's Lymphoma in Africa and the growth of smooth-muscle tumors after organ transplants. The symptoms of the EBV invention includes fatigue, low grade fever, lymphadenopathy and sore throat. Some patients experience a more severe infection with splenomegaly. EBV takes a fulminant course in patients infected with HIV. In EBV infections, once the initial episode resolves, the virus becomes latent and can be reactivated later in life. A few EBV infections remain chronically active.

To date, no effective treatment for EBV exists. Accordingly, a need for such a treatment is evident.

SUMMARY OF THE INVENTION

This invention is directed to a method of treating mammals, including humans, infected with Epstein-Barr virus by administering to a mammal in need thereof of a pharmaceutically effective amount of acyclovir, famciclovir, valacyclovir or a pharmaceutically acceptable salt thereof.

It has unexpectedly been discovered that antiviral agents acyclovir, famciclovir, and valacyclovir and a pharmaceutically acceptable salt thereof, are useful in treating mammals, including humans, infected with EBV.

DETAILED DESCRIPTION OF THE INVENTION

Antiviral agents of the present invention include acyclovir, famciclovir, valacyclovir and a pharmaceutically acceptable salt thereof. Acyclovir, famciclovir and valacyclovir have known uses for treating herpesvirus zoster (shingles) and genital herpes. Acyclovir is also indicated for treatment of chickenpox.

U.S. Pat. No. 4,199,574, incorporated herein by reference, describes the preparation of acyclovir, also known as 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one. Acyclovir is currently marketed under the trademark Zovirax.

Valacyclovir is a generic name for L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H purin-9-yl)methoxy]ethyl ester. It is the L-valine ester of acyclovir and its preparation is described in U.S. Pat. No. 4,957,924, which is incorporated herein by reference. Valacyclovir is currently marketed under the trademark Valtrex.

Famciclovir is a generic name for 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. It's preparation is described in Australian patent application No. 84 31,973 and M. R. Hamden et al., J.Med.Chem., vol. 32, 1738 (1989), which are incorporated herein by reference. Famciclovir is currently marketed in the United States under the trademark Famvir.

As defined herein, a "therapeutically effective" amount of acyclovir, valacyclovir, famciclovir or a pharmaceutically acceptable salt thereof is a non-toxic amount which alleviates the symptoms associated with EBV infection.

Furthermore, as defined herein, the phrase "method of treating" is not limited to elimination of the symptoms or elimination of the virus, but also refers to alleviation of the symptoms associated with EBV infection or deactivation of the virus. Epstein Barr virus is easily reactivated after primary infection. Many factors can contribute to reactivation of the latent Epstein Barr virus including, but not limited to, malnourishment, overwork, lack of sleep or concurrent disease. Anything that stresses the immune system allows the virus to become active. Recurrences are similar to those seen with other herpesviruses. Acyclovir, valacyclovir and famiciclovir are useful in deactivating the virus. While use of these anti-viral agents can suppress EBV effectively and provide significant symptomatic relief, it is not clear whether the virus is permanently eliminated. Thus, retreatment may be necessary in some individuals.

EBV infections are associated with several known diseases. Examples include, but are not limited to, mononucleosis, chronic fatigue syndrome, nasopharyngeal carcinoma, Burkitt's Lymphoma and the growth of smooth-muscle tumors after organ transplants.

The antiviral agent of the present invention may be administered by any suitable route including oral, rectal, nasal, topical, vaginal, parenteral. Preferred mode of administration is oral.

The antiviral agent of the present invention may be formulated into tablets, capsules or other oral dosage forms containing one or more pharmaceutically acceptable carriers, such as lactose, cornstarch, hydroxypropylmethylcellulose, microcrystalline cellulose as well as other excipients known in the art.

In addition to the aforementioned ingredients, the pharmaceutical composition of this invention may include one or more of additional ingredients, e.g., pharmaceutically acceptable carriers such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

The amount of the antiviral agents required to constitute a "therapeutically effective amount" will vary based on a number of factors, including the severity of the symptoms and the identify and chemical makeup of the patient, and a mode of administration. In the case of oral administration, the preferred dosages are as follows: for valacyclovir, 500 mg once or twice daily for two to sixteen weeks; for famciclovir, 125 mg or 250 mg, once or twice daily, for two to sixteen weeks; and for acyclovir, 200 mg once or twice daily for two to sixteen weeks.

For example, valacyclovir may be administered orally to patients in doses ranging from 500 mg once daily to 1000 mg three times per day. The dosage is dependent on the patient's weight and the extent of disease. It should be modified if renal disease is present and would reflect the level of creatinine clearance. For example, the creatinine clearance was greater than or equal to 50 ml/min, the dose preferably should not exceed 500 mg twice a day. If the creatinine clearance was between 30-49 ml/min, the dose preferably should not exceed 500 mg once a day. Mild hepatic disease does not preclude treatment with this drug. Valacyclovir should be used with supervision in patients with advanced HIV infection and in bone marrow or renal transplant patients. Pregnant females, nursing mothers or pediatric patients should not receive valacyclovir unless the risk of infection outweighs its use. The most preferred dosage is 500 mg twice a day. Preferable duration of administration is between two and sixteen weeks.

In an embodiment of the present invention, famciclovir may be given orally in doses ranging from 125 mg once daily to 5 mg three times a day. It is well understood in the art that in cases of renal impairment, the dosage should be adjusted accordingly. For instance, if a creatinine clearance is between 40-59 ml/min, the recommended maximum dose is 250 mg twice daily. If a creatinine clearance is between 20-39 ml/min, the recommended maximum dose is 250 mg once daily or 125 mg twice daily. Mild hepatic disease does not preclude treatment with famciclovir. Famciclovir is not recommended for use in pregnant women or children. Preferred duration of therapy is eight weeks. Preferred dose is 250 mg twice daily.

In another embodiment of the present invention, acyclovir may be given orally in doses from 200 mg once daily to 400 mg four times daily. Preferably, the dose should not exceed 400 mg twice daily in patients with compromised renal function. Children may be treated with acyclovir at 20 mg per kg four times per day. Children weighing more than forty kg may be dosed as an adult. Children weighing less than forty kg are rarely infected with EBV unless unusual circumstances prevail. Treatment for initial EBV infection may be 200 mg four times per day for ten days. For reactivated EBV infection in an adult, preferred dosage is 400 mg twice a day for four weeks.

The following example section describes embodiments of the present invention and should not be construed as limiting.

EXAMPLE I

Patients infected with Epstein Barr virus were treated with the antiviral agents of the present invention: acyclovir, valacyclovir and famciclovir. To confirm infection, serology was done prior to treatment using a western blot for EBV. In addition, a complete blood count to access immune system function and hematological status and chemistry analysis to check liver and kidney function prior to therapy were performed. The latter tests were repeated during and after treatment to determine the existence of adverse phenomena as a result of treatment. The EBV western blot was also repeated after therapy was completed to demonstrate efficacy. All patients displayed symptoms consistent with EBV infection, most notably fatigue.

The test group consisted of 29 patients, 18 of whom were female and 11 were male. Their ages ranged from 16 to 56. All complained of fatigue as the main symptom. 11 percent of these patients showed serological evidence of initial infection with EBV virus. The remainder were divided into 16 percent chronic infection and 72 percent reactivated EBV infection. Of the 29 patients, 3 were treated successfully with famciclovir, 25 with valacyclovir only and one with acyclovir. No patients were given a placebo.

After initial testing, patients were treated for four week intervals. Treatment ranged from administration of 500 mg valacyclovir once daily for two weeks to twice daily for 16 weeks; famciclovir from two to 16 weeks, including administration of 125 mg twice a day for 16 weeks and 250 mg once a for 8 weeks; acyclovir 200 mg a day for 8 weeks (please verify the dosage and frequency of administration information).

The patients were seen every four weeks for assessment of symptoms and to obtain serological data. The goal of therapy was resolution of symptoms. At monthly appointments, only five patients reported adverse effects; one with mild headache, two noted mild nausea and headache, and one with nausea alone. This occurred in the initial four weeks of therapy and resolved spontaneously or responded to a change in dose or medication. One patient experienced disorientation and light-headedness while taking valacyclovir but did not experience any side effects using acyclovir. It is not certain if these abnormalities were due to treatment with valacyclovir or not. No one stopped medication because of adverse effects. Repeat lab testing did not show any incidence of hepatic, renal, immune or hematological dysfinction related to use of this group of pharmaceuticals. A summary of these treatments is provided below in a table format. In this table, day 1 refers to the day the treatment began; "bid" stands for "twice a day"; and "od" stands for "once a

    __________________________________________________________________________                    ADVERSE              EBV                                        PATIENT                                                                             MEDICATION                                                                               REACTION  RESPONSE   WESTERN BLOT                               __________________________________________________________________________      1   Valacyclovir 500 mg                                                                      None      Fatigue resolved; sore                                                                    Positive on Day 1;                              od for 12 wks       throat better as of                                                                       negative approx. 2, 5                                               1/28/98; no recurring                                                                     and 7 mos from Day 1                                                symptoms                                               2   Valacyclovir 500 mg                                                                      None      Fatigue, sore throat                                                                      Positive on Day 1;                              bid for 8 wks       and swollen glands                                                                        negative approx. 5                                                  resolved; will go back                                                                    mos from Day 1;                                                     on Valacyclovir 500                                                                       positive approx. 9                                                  mg bid for 4-8 wks                                                                        mos. after Day 1                                                               (symptoms returned)                         3   Valacyclovir 500 mg                                                                      None      Fatigue finally                                                                           Positive on Day 1 and                           od for 4 wks;       improved   approx. 2 and 4 mos                             Valacyclovir 500 mg            from Day 1; negative                            bid for 4 wks;                 approx. 8 mos from                              Famciclovir 125 mg             Day 1                                           bid for 16 wks                                                             4   Valacyclovir 500 mg                                                                      None      Fatigue improved                                                                          Positive on Day 1;                              od for 12 wks;                 negative approx. 5                              Famciclovir 250 mg             mos. from Day 1                                 od for 8 wks                                                               5   Valacyclovir 500 mg                                                                      None      Symptoms improve                                                                          Positive on Day 1;                              od - BID            then reoccur; minor                                                                       positive approx. 4                              intermittently over 1                                                                              changes in test results;                                                                  mos. and 8 mos from                             yr; 4-8 wks at a time                                                                              Valacyclovir allows                                                                       Day 1                                                               patient to resume                                                              work and function;                                                             chronic infection                                      6   Valacyclovir 500 mg                                                                      None      Significant                                                                               Positive on Day 1;                              od for 4 wks, then  improvement after                                                                         negative approx. 4                              Valacyclovir 500 mg increasing dose to bid -                                                                  mos. from Day 1                                 bid for 8 wks       fatigue vastly                                                                 improved, even                                                                 exercising                                             7   Valacyclovir 500 mg                                                                      None      Significant                                                                               Positive on Day 1 and                           od for 4 wks;       improvement; initially                                                                    approx. 4 and 7 mos.                            Valacyclovir 500 mg patient unable to work -                                                                  from Day 1                                      bid for 12 wks;     now working full                                           Valacyclovir 500 mg time and caring for                                        tid for 12 wks      family; minimal lab                                                            changes                                                8   Valacyclovir 500 od                                                                      None      EBV panel -; major                                         for 16 week;        decrease in                                                Valacyclovir 500 bid                                                                               symptoms; no benefit                                       for 2 weeks         from inc to bid;                                                               weaned off                                             9   Valacyclovir 500 od                                                                      None      Transient relief of                                        to bid for 4-6 weeks                                                                               symptoms with                                                                  reoccurences; chronic,                                                         remitting with meds,                                                           EBV.                                                  10   Valacyclovir 500 od                                                                      Slight nausea initially -                                                                Fatigue gone;                                              for 8 weeks                                                                              resolved in one week                                                                     decreased antibody                                    11   Valacyclovir 500 bid                                                                     None      Fatigue, sore throat                                       for 8 weeks         gone; EBV ab down                                     12   Valacyclovir 500 for                                                                     None      Valacyclovir lessened                                      4 weeks - famiclovir                                                                               fatigue slightly.                                          250 mg od           Famiclovir improved                                                            energy and sore throat                                13   Valacyclovir 500 od                                                                      None      Significant                                                for 4 weeks;        improvement -                                              Valacyclovir 500 bid                                                                               fatigue, sore throat.                                      for 12 weeks;       Lasts for several                                          Valacyclovir 500 od months and reoccurs.                                       for 4 weeks                                                               14   Valacyclovir 500 od                                                                      Headache and nausea                                                                      Fatigue and sore                                           for 1.5 weeks - felt                                                                     with Valacyclovir - pt                                                                   throat and swollen                                         nauseous and HA -                                                                        stopped 2.5 weeks                                                                        glands much                                                switched to acyclovir                                                                    later started acyclovir                                                                  improved - EBV ab                                          200 od for 8 weeks -                                                                     200 od without                                                                           level unchanged.                                           tolerated this well.                                                                     problem   Symptomatic                                           15   Valacyclovir 500 bid                                                                     None      Fatigue, sore throat                                       for 8 weeks         and swollen glands                                                             gone                                                  16   Valacyclovir 500 bid                                                                     None      Fatigue significantly                                      for 8 weeks         improved; EBV ab                                                               decreased                                             17   Valacyclovir 500 od                                                            for 4 weeks                                                               18   Valacyclovir 500 mg                                                                      --                   Positive on Day 1;                              od for 4 wks                   positive approx. 10                                                            mos from Day 1                             19   Valacyclovir 500 mg                                                                      Headache if taken                                                                        Fatigue significantly                                                                     Positive on Day 1;                              od for 4 wks, 2 wk                                                                       longer than 2 wks; no                                                                    reduced; decreased                                                                        negative approx. 2                              intervals headache if taken for                                                                    EBV antibodies                                                                            mos from Day 1                                            2 wks; off for 2 wks;                                                          then repeat 2 wks of                                                           Valacyclovir                                                    20   Valacyclovir 500 mg                                                                      None      Fatigue significantly                                                                     Positive on Day 1; no                           bid for 4 wks       improved   retest                                     21   Valacyclovir 500 mg                                                                      None      Fatigue improved -                                                                        Positive on Day 1;                              bid for 4 wks;      patient able to                                                                           negative approx. 2                              Valacyclovir 500 mg exercise - EBV;                                                                           mos from Day 1                                  od for 4 wks        intermittently active                                                          infection - suppressed                                                         each time with                                                                 Valacyclovir                                          22   Valacyclovir 500 mg                                                                      None      Resolution of fatigue                                                                     Positive on Day 1;                              od for 16 wks       and sore throat; EBV                                                                      negative approx. 4                                                             mos from Day 1                             23   Valacyclovir 500 mg                                                                      None      Resolution of fatigue,                                                                    Positive on Day 1;                              od for 12 wks;      sore throat and                                                                           negative approx. 6                              Valacyclovir 500 mg swollen glands; EBV                                                                       mos from Day 1                                  bid for 8 wks                                                             24   Valacyclovir 500 mg                                                                      None      Fatigue and sore                                                                          Positive on Day 1;                              bid for 8 wks       throats significantly                                                                     negative approx. 14                                                 reduced; EBV titer                                                                        mos from Day 1                                                      negative - not done                                                            for 1 yr but symptoms                                                          gone within 8 wks                                     25   Valacyclovir 500 mg                                                                      None at this rate; if                                                                    Fatigue gone; EBV                                                                         Positive on Day 1;                              od for 2 wks; then                                                                       higher headache and                                                                      titer negative                                                                            negative approx. 5                              Valacyclovir od every                                                                    nausea               mos from Day 1                                  other day for 3 wks                                                       26   Valacyclovir 500 mg                                                                      None      Fatigue improved                                                                          Positive on Day 1; no                           od for 2 wks        after first 2 wk                                                                          retest                                                              interval                                              27   Valacyclovir 500 mg                                                                      None      Fatigue, sore throat                                                                      Positive on Day 1;                              bid for 12 wks      and swollen glands                                                                        negative 6 mos from                                                 gone; EBV negative                                                                        Day 1                                      28   Famciclovir 250 for 8                                                                    None      Clinically improved;                                       weeks bid           EBV titer negative                                    29   Famvir 250 od for 4                                                                      None      Significant clinical                                       weeks               improvement                                           30   Valacyclovir 500 mg                                                                      None      EBV panel; major                                                                          Positive on Day 1;                              od for 16 wks;      decrease in                                                                               negative approx. 11                             Valacyclovir 500 mg symptoms; no benefit                                                                      mos from Day 1                                  bid for 2 wks       when dosage                                                                    increased to bid;                                                              weaned off                                            31   Valacyclovir 500 mg                                                                      None      Transient relief of                                                                       Positive on Day 1;                              od to BID for 4-6 wks                                                                              symptoms with                                                                             positive approx. 5 and                                              reoccurrences;                                                                            7 mos from Day 1                                                    chronic, remitting                                                             with meds, EBV                                        32   Valacyclovir 500 mg                                                                      Slight nausea initially -                                                                Fatigue gone;                                                                             Positive on Day 1 and                           od for 8 wks                                                                             resolved in one wk                                                                       decreased antibody                                                                        approx. 3 mos from                                                             Day 1; negative                                                                approx. 7 mos from                                                             Day 1                                      33   Valacyclovir 500 mg                                                                      None      Fatigue, sore throat                                                                      Positive on Day 1;                              bid for 8 wks       gone; EBV antibody                                                                        negative approx. 2                                                  down       mos from Day 1                             34   Valacyclovir 500 mg                                                                      None      Valacyclovir lessened                                                                     Positive on Day 1; no                           for 4 wks -         fatigue slightly;                                                                         retest                                          Famciclovir 250 mg  Famciclovir improved                                       od                  energy and sore throat                                35   Valacyclovir 500 mg                                                                      None      Significant                                                                               Positive on Day 1 and                           od for 4 wks;       improvement, fatigue,                                                                     approx. 3 mos from                              Valacyclovir        sore throat; lasts for                                                                    Day 1; negative                                 5000BID for 12 wks; several mos and                                                                           approx. 7 mos from                              Valacyclovir 500 mg reoccurs   Day 1                                           od for 4 wks                                                              36   Valacyclovir 500 mg                                                                      Headache and nausea                                                                      Fatigue and sore                                                                          Positive on Day 1 and                           od 1or 1.5 wks; felt                                                                     with Valacyclovir - pt                                                                   throat and swollen                                                                        approx. 1 mo and 6                              nauseous and HA -                                                                        stopped - 2.5 wks                                                                        glands much                                                                               mos from Day 1                                  switched to Zovirax                                                                      later started Zovirax                                                                    improved - EBV                                             200 mg od for 8 wks;                                                                     200 mg od without                                                                        antibody level                                             tolerated this well                                                                      problem   unchanged;                                                                     symptomatic                                                                    improvement only                                      37   Valacyclovir 500 mg                                                                      None      Fatigue, sore throat                                                                      Positive on Day 1;                              bid for 8 wks       and swollen glands                                                                        negative approx. 4                                                  gone       mos from Day 1                             38   Valacyclovir 500 mg                                                                      None      Fatigue significantly                                                                     Positive on Day 1;                              bid for 8 wks       improved; EBV                                                                             negative approx. 3                                                  antibody decreased                                                                        mos from Day 1                             39   Valacyclovir 500 mg                                                                      Could not tolerate bid                                                                   Fatigue, sore throat                                                                      Positive on Day 1                               od for 6 wks                                                                             dose 2 mos. earlier                                                                      gone       and approx. 2 months                                      and had stopped after                                                                               from Day 1; no retest                                     a few days because of                                                          nausea; tolerated od                                                           dose without                                                                   problems                                                        40   Valacyclovir 500 mg                                                                      None      Fatigue, sore throat,                                                                     Positive on Day 1; no                           od for 8 wks;       flu-like symptoms;                                                                        retest                                          Valacyclovir 500 mg much improved                                              bid for 4 wks                                                             41   Valacyclovir 500 mg                                                                      None      Fatigue significantly                                                                     Positive on Day 1;                              bid for 8 wks       improved   negative approx. 2                                                             months from Day 1                          42   Valacyclovir 500 bid x                                                                   None      Fatigue; sore throat                                       12 wks              and swollen glands                                                             gone; EBV -                                           43   Valacyclovir 500 od x                                                                    None      Fatigue decreased                                          12 wks              significantly.                                        44   Valacyclovir 500 bid x                                                                   None      Fatigue was improved                                       12 wks              but in this case it is                                                         not clear whether the                                                          patient experienced                                                            relief because of the                                                          effect of Valacyclovir                                                         on EBV or not. Her                                                             EBV titer did not                                                              change. Intraoral                                                              blisters healed.                                                               Herpes Simplex ab                                                              testing for IgM                                                                component negative                                    45   Valacyclovir 500 od x                                                                    None      Fatigue, sore throat                                       4 wks               and swollen glands                                                             improved.                                             46   Famciclovir 250 mg                                                                       Headache  Significant decrease                                       x 4 wks.            in fatigue                                            47   Famciclovir 250 od x                                                                     None      Decreased clinical                                         2 wks               symptoms; negative                                                             test results                                          48   Famciclovir 125 mg                                                                       None      Clinical improvement                                       bid x 8 wks                                                               49   Famciclovir 250 mg                                                                       None      Clinical improvement.                                      bid for 3 wks x 2   EBV titer pending.                                    50   Valacyclovir 500 bid                                                                     None      1. Awake but                                               x 4 wks; Famciclovir                                                                               unable to do                                               250 x 4 wks;        anything.                                                  Valacyclovir 500 Tid                                                                               2. Worse                                                   x 2 wks; Valacyclovir                                                                              3. Better                                                  500 x 4 wks         4. Awake all day                                                               and starting to do                                                             light activity.                                       51   Famciclovir 500 bid                                                                      None      Clinical improvement                                  52   Valacyclovir 500 bid                                                                     None      Clinical improvement;                                      x 8 wks             Neg test                                              53   Valacyclovir 500 bid                                                                     None      Clinical improvement                                       x 8 weeks                                                                 54   Valacyclovir 500 od x                                                                    None      Clinical improvement                                       4 wks; Valacyclovir                                                            500 bid x 8 wks                                                           55   Valacyclovir 500 bid                                                                     None      Significant clinical                                       x 16 wks;           improvement despite                                        Valacyclovir 500 od x                                                                              decrease                                                   12 wks; Valacyclovir                                                           500 od every 3.sup.rd day                                                 56   Valacyclovir 500 bid                                                                     None      Clinical improvement                                       x 8 wks                                                                   57   Famciclovir 125 TID                                                                      None after initial 2                                                                     Clinical improvement                                       x 7 wks   days (nervous)                                                                           and negative test                                                              results                                               58   Famciclovir 250 tid x                                                                    None      Clinical improvement                                       6 wks               and negative test                                                              results                                               59   Famciclovir 250 bid x                                                                    None      Clinical improvement                                       6 wks               and negative results.                                 __________________________________________________________________________ 

What is claimed is:
 1. A method for treating mononucleosis in a patient which comprises administering to the patient in need thereof an effective therapeutic amount of the drug famcyclovir or a pharmaceutically acceptable salt thereof.
 2. The method according to claim 1, wherein the effective therapeutic amount of the drug administered to the patient is 50 to 500 milligrams.
 3. The method according to claim 1, wherein the effective therapeutic amount of the drug is administered to the patient one to two times a day.
 4. The method according to claim 1, wherein the effective therapeutic amount of drug is administered to the patient for two to sixteen weeks. 